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Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-? signaling.

ABSTRACT: The Hippo pathway is involved in intestinal epithelial homeostasis with Wnt, BMP, Notch, and EGF signaling. We investigated the relationship between Hippo and other signaling pathways and the role of MOB kinase activator 1A/1B (MOB1A/B) in intestinal homeostasis. Mice with intestinal epithelial cell (IEC)-specific depletion of MOB1A/B showed hyperproliferation in IECs, defects in secretory lineage differentiation and loss of intestinal stem cells and eventually died at 10-12 days after tamoxifen treatment. In MOB1A/B-depleted IECs, expression of Wnt target genes were downregulated but Bmp2 and Tgfbr2 were transcriptionally activated with enhanced YAP activity. In in vivo and in vitro experiments with several signaling inhibitors, it has been shown that the BMP inhibitor LDN193189 or TGF-? inhibitor SB431542 had effects on partial restoration of the intestinal degenerative phenotype. Treatment with these inhibitors restored differentiation of secretory lineage cells in MOB1A/B-deficient mice, but not ISC pools in the crypt region. These studies reveal that IEC-specific depletion of MOB1A/B induced overexpression of Bmp2 and Tgfbr2 and inhibited Wnt activity, finally leading to loss of ISCs and functional epithelia in the mouse intestine. These results suggest that MOB1A/B has an essential function for intestinal epithelial homeostasis by regulating YAP, Wnt activity, and BMP/TGF-? signaling.

SUBMITTER: Bae JS

PROVIDER: S-EPMC6197243 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-β signaling.

Bae June Sung JS Jeon Yoon Y Kim Sun Mi SM Jang Ji Yun JY Park Mi Kyung MK Kim In-Hoo IH Hwang Deog Su DS Lim Dae-Sik DS Lee Ho H

Cell death & disease 20181022 11

The Hippo pathway is involved in intestinal epithelial homeostasis with Wnt, BMP, Notch, and EGF signaling. We investigated the relationship between Hippo and other signaling pathways and the role of MOB kinase activator 1A/1B (MOB1A/B) in intestinal homeostasis. Mice with intestinal epithelial cell (IEC)-specific depletion of MOB1A/B showed hyperproliferation in IECs, defects in secretory lineage differentiation and loss of intestinal stem cells and eventually died at 10-12 days after tamoxifen ...[more]

PMID: 30349003

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Project description:BackgroundThe clinical healing environment after a posterior spinal arthrodesis surgery is one of the most clinically challenging bone-healing environments across all orthopedic interventions due to the absence of a contained space and the need to form de novo bone. Our group has previously reported that sclerostin in expressed locally at high levels throughout a developing spinal fusion. However, the role of sclerostin in controlling bone fusion remains to be established.MethodsWe computationally identified two FDA-approved drugs, as well as a single novel small-molecule drug, for their ability to disrupt the interaction between sclerostin and its receptor, LRP5/6. The drugs were tested in several in vitro biochemical assays using murine MC3T3 and MSCs, assessing their ability to (1) enhance canonical Wnt signaling, (2) promote the accumulation of the active (non-phosphorylated) form of β-catenin, and (3) enhance the intensity and signaling duration of BMP signaling. These drugs were then tested subcutaneously in rats as standalone osteoinductive agents on plain collagen sponges. Finally, the top drug candidates (called VA1 and C07) were tested in a rabbit posterolateral spine fusion model for their ability to achieve a successful fusion at 6 wk.ResultsWe show that by controlling GSK3b phosphorylation our three small-molecule inhibitors (SMIs) simultaneously enhance canonical Wnt signaling and potentiate canonical BMP signaling intensity and duration. We also demonstrate that the SMIs produce dose-dependent ectopic mineralization in vivo in rats as well as significantly increase posterolateral spine fusion rates in rabbits in vivo, both as standalone osteogenic drugs and in combination with autologous iliac crest bone graft.ConclusionsFew if any osteogenic small molecules possess the osteoinductive potency of BMP itself - that is, the ability to form de novo ectopic bone as a standalone agent. Herein, we describe two such SMIs that have this unique ability and were shown to induce de novo bone in a stringent in vivo environment. These SMIs may have the potential to be used in novel, cost-effective bone graft substitutes for either achieving spinal fusion or in the healing of critical-sized fracture defects.FundingThis work was supported by a Veteran Affairs Career Development Award (IK2-BX003845).

Dataset Information

Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-? signaling.

Publications

Depletion of MOB1A/B causes intestinal epithelial degeneration by suppressing Wnt activity and activating BMP/TGF-β signaling.

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